Efficacy study for Huntington's drug made possible

The potential Huntington's drug RG6042 has shown in a placebo-controlled clinical study with 46 patients to not cause any serious side effects while reducing the amount of the harmful protein huntingtin in the spinal fluid depending on the dose.

No serious side effects observed with RG6042

The potential Huntington's drug RG6042 has been shown in a clinical study to be tolerated and reduces the amount of the harmful protein huntingtin in the spinal fluid depending on the dose. In the placebo-controlled study with 46 patients, it was found that the substance does not cause any serious side effects. 

Due to the short duration of treatment, the study is not yet able to provide any information on the clinical efficacy of the drug. "We hope that Huntington's disease will progress less rapidly thanks to the drug and that symptoms may even disappear," said Prof. Dr. G. Bernhard Landwehrmeyer, a neurologist from Ulm and head of the clinical study in Germany. The results on tolerability are reported by the researchers in the New England Journal of Medicine.

Tenuous side effects

The drug was administered via lumbar puncture directly into the spinal fluid. 12 of the 46 patients received a placebo. For the other participants, the dose was gradually increased in the course of the study in different cohorts. Severe side effects were not observed. Some people complained of mild headaches, but these also occurred in the placebo group. "This is the typical side effect of a lumbar puncture, and cannot be attributed to the active ingredient," explains Carsten Saft, head of the clinical division at the Huntington Center in Bochum.

Substance reduces brain exposure to defective gene products

The researchers also observed that the drug reduced the amount of the protein huntingtin in the cerebrospinal fluid - an indication that the substance works as intended. "However, we are not yet in a position to make any statements on clinical efficacy," emphasizes Carsten Saft. "The number of patients was too small for that."

The aim is for the active substance to reduce the amount of defective huntingtin gene products and also the defective protein huntingtin in brain tissue; however, the amount of protein cannot be determined directly in the brain, but only indirectly in the spinal fluid. "If it is possible to reduce the Huntington's protein, one can also consider treating family members who have not yet contracted the disease and who carry the corresponding genetic modification," said Bernhard Landwehrmeyer.

Further studies planned

A larger study has just begun to test the clinical efficacy of the drug (Phase III study). For this worldwide study, about 660 participants are to be recruited, to whom the drug will be administered at regular intervals over two years by lumbar puncture directly into the spinal fluid.

On the basis of these data, the physicians also want to investigate changes that they have not been able to clearly interpret so far, for example, an unexpected change in the brain ventricles, which they observed in the patients in the current study.

Sarah J. Tabrizi et al.: Targeting Huntingtin expression in patients with Huntington's Disease, in: New England Journal of Medicine, 2019, DOI: 10.1056/NEJMoa1900907